Development of multiplexed bead-based immunoassays for the detection of early stage ovarian cancer using a combination of serum biomarkers

CA125 as a biomarker of ovarian cancer is ineffective for the general population. The aim of this study was to evaluate multiplexed bead-based immunoassay of multiple ovarian cancer-associated biomarkers such as transthyretin and apolipoprotein A1, together with CA125, to improve the identification and evaluation of prognosis of ovarian cancer. We measured the serum levels of CA125, transthyretin, and apolipoprotein A1 from the serum of 61 healthy individuals, 84 patients with benign ovarian disease, and 118 patients with ovarian cancer using a multiplex liquid assay system, Luminex 100. The results were then analyzed according to healthy and/or benign versus ovarian cancer subjects. When CA125 was combined with the other biomarkers, the overall sensitivity and specificity were significantly improved in the ROC curve, which showed 95% and 97% sensitivity and specificity, respectively. At 95% specificity for all stages the sensitivity increased to 95.5% compared to 67% for CA125 alone. For stage I+II, the sensitivity increased from 30% for CA125 alone to 93.9%. For stage III+IV, the corresponding values were 96.5% and 91.6%, respectively. Also, the three biomarkers were sufficient for maximum separation between noncancer (healthy plus benign group) and stage I+II or all stages (I-IV) of disease. The new combination of transthyretin, and apolipoprotein A1 with CA125 improved both the sensitivity and the specificity of ovarian cancer diagnosis compared with those of individual biomarkers. These findings suggest the benefit of the combination of these markers for the diagnosis of ovarian cancer.     

Improvement of long-term prognosis in patients with ovarian cancers by adjuvant sizofiran immunotherapy: a prospective randomized controlled study

The effect of immunotherapy using sizofiran (SPG) on the prognosis of patients with ovarian cancers was prospectively studied in a total of 68 patients, who were randomly assigned to either a cisplatin, adriamycin and cyclophosphamide (PAC) therapy group or a PAC plus SPG combination therapy group.The survival rate was significantly higher in patients with stage Ic, II or III cancers treated with the PAC plus SPG combination, compared with the patients treated with PAC alone. In the SPG-receiving patients with stage Ic or more advanced cancers who were treated with four cycles or more of PAC, the outcome was improved (Cox-Mantel, p=0.074; generalized Kruskal-Wallis, p=0.032). Similar improvement was also observed in the patients with non-serous adenocarcinomas (Cox-Mantel, p-0.076; generalized Krukal-Wallis, p=0.045). No side effects attributable to SPG were recorded.The present results suggest that the use of SPG in combination with long-term chemotherapy improves the postoperative prognosis in ovarian cancer patients.Abbreviations SPG sizofiran     

Screening for early familial ovarian cancer with transvaginal ultrasonography and colour blood flow imaging.

OBJECTIVE--To assess the value of transvaginal ultrasonography with colour blood flow imaging in detecting early ovarian cancer in women with a family history of the disease. DESIGN--Study of self referred symptomless women with a close relative who had developed the disease. Each woman was screened to detect persistent lesions and defined changes in ovarian volume. Morphological score and pulsatility index were recorded. SETTING--Ovarian screening clinic. SUBJECTS--1601 self referred women. INTERVENTIONS--Women with a positive screening result were recommended to have further investigations. MAIN OUTCOME MEASURES--Findings at surgery and histology of abnormal ovaries. Morphological score > or = 5 and pulsatility index < 1.0 at last scan. RESULTS--Women were aged 17 to 79 (mean 47) years; 959 (60%) were premenopausal, 469 (29%) were naturally postmenopausal, and 173 (11%) had had a hysterectomy. 157 women had a pedigree suggestive of the site specific ovarian cancer syndrome and 288 of multiple site cancers. 61 women had a positive screening result (3.8%, 95% confidence interval 2.9 to 4.9%), six of whom had primary ovarian cancer detected at surgery (five stage Ia, one stage III). Use of a high morphological score or a low pulsatility index increased the odds of finding ovarian cancer from 1:9 to about 2:5 (1:1 in the highest risk groups). Five interval cancers were reported (three ovarian and two peritoneal). Eight of the 11 cancers developed in women with pedigrees suggestive of inherited cancer. CONCLUSIONS--Transvaginal ultrasonography with colour flow imaging can effectively detect early ovarian cancer in women with a family history of the disease. The screening interval should be less than two years.     

Identification and Confirmation of Differentially Expressed Fucosylated Glycoproteins in the Serum of Ovarian Cancer Patients Using a Lectin Array and LC-MS/MS

In order to discover potential glycoprotein biomarkers in ovarian cancer, we applied a lectin array and Exactag labeling based quantitative glycoproteomics approach. A lectin array strategy was used to detect overall lectin-specific glycosylation changes in serum proteins from patients with ovarian cancer and those with benign conditions. Lectins, which showed significant differential response for fucosylation, were used to extract glycoproteins that had been labeled using isobaric chemical tags. The glycoproteins were then identified and quantified by LC-MS/MS, and five glycoproteins were found to be differentially expressed in the serum of ovarian cancer patients compared to benign diseases. The differentially expressed glycoproteins were further confirmed by lectin-ELISA and ELISA assay. Corticosteroid-binding globulin (CBG), serum amyloid p component (SAP), complement factor B (CFAB), and histidine-rich glycoprotein (HRG) were identified as potential markers for differentiating ovarian cancer from benign diseases or healthy controls. A combination of CBG and HRG (AUC = 0.825) showed comparable performance to CA125 (AUC = 0.829) in differentiating early stage ovarian cancer from healthy controls. The combination of CBG, SAP, and CA125 showed improved performance for distinguishing stage III ovarian cancer from benign diseases compared to CA125 alone. The ability of CBG, SAP, HRG, and CFAB to differentiate the serum of ovarian cancer patients from that of controls was tested using an independent set of samples. Our findings suggest that glycoprotein modifications may be a means to identify novel diagnostic markers for detection of ovarian cancer.     

Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and ultrasonography.

OBJECTIVE--To assess the performance of the sequential combination of serum CA 125 measurement and ultrasonography in screening for ovarian cancer. DESIGN--The serum CA 125 concentration of each subject was determined and those with a concentration > or = 30 U/ml were recalled for abdominal ultrasonography. If ultrasonography gave abnormal results surgical investigation was arranged. Volunteers were followed up by annual postal questionnaire. SETTING--General practice, occupational health departments, ovarian cancer screening clinic. SUBJECTS--22,000 women volunteers who were postmenopausal and aged over 45 years. MAIN OUTCOME MEASURES--Apparent sensitivity, specificity, positive predictive value, years of cancer detected. RESULTS--41 women had a positive screening result and were investigated surgically. 11 had ovarian cancer (true positive result) and 30 had other disorders or no abnormality (false positive result). Of the 21,959 volunteers with a negative screening result, eight subsequently presented clinically with ovarian cancer (false negative result) and 21,951 had not developed ovarian cancer during follow up (apparent true negative result). The screening protocol achieved a specificity of 99.9%, a positive predictive value of 26.8%, and an apparent sensitivity of 78.6% and 57.9% at one year and two year follow up respectively. The estimated number of years of cancer detected by the prevalence screen was 1.4 years. CONCLUSIONS--This screening protocol is highly specific for ovarian cancer and can detect a substantial proportion of cases at a preclinical stage. Further investigation is required to determine the effect of the screening protocol on the ratio of early to late stage disease detected and on mortality from ovarian cancer.     

Transcriptional profiling develops molecular signatures for ovarian tumors.

Of the cancers unique to women, ovarian cancer has the highest mortality rate. Over 26,000 women are diagnosed with this disease in the U.S. annually, and 60% of those diagnosed will die of the disease. One of the greatest problems with this disease is the lack of strong early warning signs or symptoms resulting in advanced stage at presentation in most women, followed by the outgrowth of chemotherapy-resistant disease in the majority of patients. The 5-year survival for patients with early stage disease ranges from 50-90%, but it is less than 25% for advanced-stage disease. In collaboration with researchers at Millennium Predictive Medicine (Cambridge, MA), the Ovarian Cancer Program of the Mayo Clinic Cancer Center analyzed gene expression in over 50 primary ovarian tumors, as compared with normal ovarian epithelial cells. The technologies utilized included microarray analysis with nitrocellulose filters containing 25,000 arrayed human cDNAs, as well as the construction of subtraction suppression hybridization cDNA libraries and their subsequent sequencing. Our specific focus has been on genes that are underexpressed during the development of ovarian cancer, although this analysis has revealed a large number of consistently up- and down-regulated genes. There were more down-regulated genes in ovarian tumors than up-regulated genes. In addition, the number of genes that had altered expression levels was quite large. For example, we found 409 genes down-regulated at least 5-fold, and 72 genes up-regulated at least 5-fold in 33% of the tumors analyzed. We also observed that most of the expression alterations observed in later stage (Stages III/IV) tumors were also observed in early-stage tumors (Stages I/II). This was corroborated using comparative genomic hybridization analysis on the same tumors that were expression profiled. This analysis revealed that the late-stage tumors had more gene amplification than early-stage tumors, but most regions of change (either increases or decreases) were in common between different stage tumors. We also have verified the altered expression levels of several of these genes using several complementary strategies. Finally, we are taking top candidate genes that are consistently under-expressed in ovarian tumors and attempting to determine their functional role in the development of ovarian cancer.     

Endometrial aspiration cytology for diagnosis of peritoneal lesions in extrauterine malignancies

OBJECTIVE: To evaluate the usefulness of endometrial aspiration cytology for assessing malignant cells of extrauterine origin. STUDY DESIGN: Endometrial cytology was performed on 224 patients with primary ovarian cancer, 10 with fallopian tube cancer and 45 with peritoneal tumors. RESULTS: Of 224 patients with ovarian cancer, 53 (23.7%) had positive endometrial cytology. Positive rates were: stage I, 4.3%; stage II, 25.0%; stage III, 39.7%; stage IV, 34.5%. Histologic positive rates were: serous, 28.7%; mucinous, 11.4%; clear cell, 23.1%; endometrioid and unclassifiable adenocarcinomas, 28.0%. Of 5 patients with ovarian cancer, 2 were asymptomatic, but aspiration cytology was positive. Of 10 patients with fallopian tube cancer, 9 (90.0%) had positive endometrial cytology. The positive rate on endometrial cytology was 56.7% in stomach cancer, 60.0% in breast cancer and 20.0% in colon cancer. Of 1,209 women with stomach cancer, 30 (2.4%) displayed ovarian metastasis. Of these, 7 (23.3%) had Krukenberg's tumor; endometrial cytology was positive in 1 (14.3%). In 7 of 17 patients with positive endometrial cytology, clinical diagnosis was made before stomach cancer therapy. CONCLUSION: Endometrial aspiration cytology is useful for identifying nongynecologic malignant cells, diagnosing ovarian and fallopian tube cancers, and determining peritoneal dissemination and metastasis originating from gastrointestinal and breast cancers.     

Net survival in recurrence-free colon cancer patients

PurposeConditional net survival in recurrence-free patients (CNS-RF) provides relevant clinical information and has never been assessed yet in a non-selected colon cancer population. We aimed to estimate conditional 5-year net survival in recurrence-free patients with colon cancer in the population-based Digestive Cancer Registry of Burgundy (France).MethodsCNS-RF was estimated in the 3736 patients resected for cure for primary colon cancer between 1976 and 2006, using a flexible parametric model of net survival for every additional year survived at diagnosis and from 1 to 5 years thereafter.ResultsThe net probability of surviving 5 more years increased from 72% at diagnosis to 92% for recurrence-free patients who survived 5 years after diagnosis. CNS-RF was over 90% 3 years after diagnosis in patients aged 75 and below. CNS-RF was over 95% in patients diagnosed after 2000 who were recurrence-free 3, 4 or 5 years after diagnosis. CNS-RF was similar between patients with stage I and II disease from 2 years after diagnosis and patients with stage III disease from 5 years after diagnosis. The initial differences in net survival related to gross features, clinical presentation, number of harvested nodes in stage II, and number of involved nodes in stage III disappeared after 2 years.ConclusionsCNS-RF is a relevant measure of prognosis in patients who have already achieved a period of remission. Providing an updated estimation of prognosis in the years following diagnosis may improve the survivors’ quality of life and access to credit or insurance.     

Expression Loss and Revivification of RhoB Gene in Ovary Carcinoma Carcinogenesis and Development

RhoB, a member of small GTPases belonging to the Ras protein superfamily, might have a suppressive activity in cancer progression. Here, expression of RhoB gene was evaluated in human benign, borderline and malignant ovary tumors by immunostaining, with normal ovary tissue as control. Malignant tumors were assessed according to Federation Internationale de Gynecologie Obstetrique (FIGO) guidelines and classified in stage I-IV. Revivification of RhoB gene was investigated by analyzing the effect of histone deacetylase (HDAC) inhibitor trichostatin (TSA) and methyltransferase inhibitor 5-azacytidine (5-Aza) on ovarian cancer cells via RT-PCR and western blot. Apoptosis of ovary cancer cells was detected using flowcytometry and fluorescence microscopy. Subsequently, RhoB expression is detected in normal ovary epithelium, borderline tumors, and decreases significantly or lost in the majority of ovarian cancer specimen (P<0.05). RhoB expression decreases significantly from stage II (71.4%) to stage III (43.5%) to stage IV (18.2%, P<0.05). TSA can both significantly revive the RhoB gene and mediate apoptosis of ovarian cancer cells, but 5-Aza couldn’t. Interference into Revivification of RhoB gene results in reduction of ovary carcinoma cell apoptosis. It is proposed that loss of RhoB expression occurs frequently in ovary carcinogenesis and progression and its expression could be regulated by histone deacetylation but not by promoter hypermethylation, which may serve as a prospective gene treatment target for the patients with ovarian malignancy not responding to standard therapies.     

Experience with the treatment of advanced pancreatic cancer in Hungary

In the first phase of this study 34 patients with advanced pancreatic cancer have been treated either with gemcitabine/cisplatin or gemcitabine/5-fluorouracil (5FU)/leucovorin combination. (Gemzar: 900 mg/m2, Cisplatin: 20 mg/m2, 5-FU: 750 mg/m2). Treatments were continued till tumor progression. There was no difference observed between the two protocols in the clinical response rates (PR=65%). On the other hand, a significant difference was found between the two protocols regarding the side effects. In the case of gemcitabine/5-FU neutropenia, thrombocytopenia and anaemia (as well as nausea and vomiting) were much less frequent compared to gemcitabine/cisplatin combination. Based on these data the efficacy of gemcitabine/5-FU combination was evaluated in 99 stage III, T1-4, N1 and stage IV, T1-4, N0-1, M1 pancreatic cancer patients throughout 364 treatment cycles. OR was achieved in 10% while stable disease in 52% of the cases. The average survival period was 8.33 months while the time to progression was 5.75 months. Based on these data we recommend gemcitabine/5-FU/leucovorin combination for the treatment of advanced pancreatic cancer.     

Treatment of persistent knee effusions with intra-articular radioactive gold.

Patients with a total of 112 chronic knee effusions unresponsive to the usual conservative methods of therapy were treated with intra-articular injections of radioactive gold and followed from 6 months to 5 years. Most patients in the study had rheumatoid arthritis but others had ankylosing spondylitis, psoriatic arthritis, intermittent hydrathrosis and undiagnosed synovitis. After 6 months 81% showed improvement. This figure diminished to approximately 70% at 1 and 2 years, 60% at 3 and 4 years and 50% at 5 years. The mose beneficial results were seen in patients with intermittent hydrarthrosis. Twelve patients with a synovial cyst and/or rupture improved. Patients with thin synovia and anatomic stage I or II disease did best, but those with stage III disease also did well. After the injection 33% of the patients had a reactive synovitis. A variable amount of radioactive material escaped from the knee to the regional lymph nodes and general circulation.     

Pre-treatment neutrophil to lymphocyte ratio is elevated in epithelial ovarian cancer and predicts survival after treatment

Purpose  Inflammatory cells can both suppress and stimulate tumor growth, and the influence of inflammatory cells on clinical outcome has been the focus of many studies. The purpose of this study was to evaluate the effectiveness of the neutrophil to lymphocyte ratio (NLR), a measure of the systemic inflammatory response, as an additional discriminative biomarker in epithelial ovarian cancer and to determine whether it predicts survival and recurrence. Methods  We studied 192 patients with epithelial ovarian cancer, 173 with benign ovarian tumors, 229 with benign gynecologic disease, and 405 healthy controls. Serum CA125 levels and leukocyte counts according to subtypes were recorded prior to treatment in all study subjects. In epithelial ovarian cancer, the diagnostic usefulness of NLR, in combination with CA125, was evaluated. The correlation between NLR and overall and disease-free survival was analyzed using both univariate and multivariate analyses adjusting for the known prognostic factors (age, stage, cell type, and grade). Results  Preoperative NLR in ovarian cancer subjects (mean 6.02) was significantly higher than that in benign ovarian tumor subjects (mean 2.57), benign gynecologic disease subjects (mean 2.55), and healthy controls (mean 1.98) (P < 0.001). The sensitivity and specificity of NLR in detecting ovarian cancer was 66.1% (95% CI, 59.52–72.68%) and 82.7% (95% CI, 79.02–86.38%), respectively (cutoff value: 2.60). In early stage ovarian cancer, CA125 was not elevated in 19 out of 49 patients. Seven (36.8%) of these 19 patients were NLR positive. On Cox multivariate analysis, NLR positive, stage III/IV, and older age were independent poor prognostic factors, and being NLR positive was the most powerful predictive variable (Hazard Ratio = 8.42 [95% CI: 1.09–64.84], P = 0.041). Conclusions  Our findings provide evidence for the association between NLR and epithelial ovarian cancer. Preoperative NLR, in combination with CA125, may represent a simple and cost-effective method of identifying ovarian cancers, and an elevated NLR may predict an adverse outcome in ovarian cancer.     

Transabdominal ultrasound screening for early ovarian cancer.

OBJECTIVE--To assess the value of ultrasonography in a screening procedure for early ovarian cancer. DESIGN--Prospective study of at least 5000 self referred women without symptoms of ovarian cancer. Each woman was scheduled to undergo three annual screenings (consisting of one or more scans) to detect grossly abnormal ovaries or non-regressing masses. SETTING--The ovarian screening clinic at King''s College Hospital, London. SUBJECTS--5479 Self referred women without symptoms (aged 18-78, mean age 52). INTERVENTIONS--Women with a positive result on screening were referred for laparoscopy or laparotomy, or both. MAIN OUTCOME MEASURES--Findings at surgery and from histology of abnormal ovaries. RESULTS--A total of 14,594 screenings (15,977 scans) were performed. A positive result was obtained at 338 screens (2.3%) comprising 326 subjects (5.9%). Five patients with primary ovarian cancer (four stage Ia, one stage Ib; two at first screening three at second) were identified (prevalence 0.09%). An additional four patients had metastatic ovarian cancer (three at first screening, one at second). The apparent detection rate was 100%. It was not possible to differentiate between the ultrasonic appearance of early malignant and benign tumours. The rate of false positive results for primary ovarian cancer was 3.5% at the first screening, 1.8% at the second, and 1.2% at the third. Overall the rate of false positive results was 2.3%; the specificity was 97.7% and the predictive value of a positive result on screening was 1.5%. The odds that a positive result on screening indicated the presence of an ovarian tumour, any ovarian cancer, or primary ovarian cancer were about one to two, one to 37, and one to 67 respectively. CONCLUSION--Ultrasonography can be used to screen women without symptoms for persistent ovarian masses that will include early ovarian cancer.     

The staging and treatment of epithelial ovarian cancer.

Recent advances in the staging of ovarian cancer have suggested that many patients with apparently localized (stage I or II) disease have occult dissemination within the abdomen. Approximately 20% of patients classified at laparotomy as having stage I or II ovarian cancer are found by lymphangiography to have abnormal retroperitoneal lymph nodes. In many other patients advanced disease is also detected by peritonescopy; with this technique metastases are often discovered on the undersurface of the right diaphragm. These findings may help explain the high rates of recurrence after surgical resection or pelvic irradiation, or both, in patients with localized disease. Studies are in progress to determine whether modification of the radiotherapy field to include the right diaphragm will improve survival. Along with improved staging, histologic grading of the degree of anaplasia of the tumour tissue may permit more precise determination of prognosis and therefore better design of therapy. Adjuvant radiotherapy has not yet been shown to improve the survival of patients with stage I disease, but the 5-year survival of patients with stage II disease is greater for those receiving postoperative radiotherapy than for those undergoing surgery alone. For most patients with advanced disease radiotherapy is palliative only and carries a high risk of long-term complications. Numerous chemotherapeutic agents used singly can produce an objective response by tumour. Preliminary data suggest that combination chemotherapy can increase the rate of objective response, but a longer follow-up period is necessary to determine whether this form of therapy can improve survival.     

Regional trends of minimally invasive radical hysterectomy for cervical cancer and exploration of perioperative outcomes

IntroductionRadical hysterectomy (RH) with bilateral pelvic lymph node dissection is the standard treatment for early stage cervical cancer which can be performed either by an abdominal or a minimally invasive (MIS) approach. In 2018, Ramirez et al. presented their randomized-controlled trial data which demonstrated that patients who were treated with minimally invasive surgical (MIS) radical hysterectomy (RH) had higher rates of locoregional disease recurrence and lower rates of overall survival when compared to patients treated with an abdominal approach. The objective of this study is to examine the trends in management of patients diagnosed with cervical cancer in New York State (NYS) and to analyze their perioperative outcomes.MethodsUsing the Statewide Planning and Research Cooperative System (SPARCS) Database, patients undergoing RH for early stage cervical cancer in NYS between the years of 2007–2015 were identified and categorized based on surgical approach. Demographic information was collected and multivariable regression was conducted to assess the impact of hysterectomy approach on perioperative outcomes.ResultsIn NYS, 5575 patients were treated with RH for early stage cervical cancer with 3257 (58.4%) treated by abdominal RH and 2318 (41.6%) treated with MIS RH. Between the years of 2007 and 2015, patients diagnosed with cervical cancer treated with MIS RH increased from 25.7% to 48.3% respectively. Surgeons performing MIS RH were more likely to be younger (average age 47.1 vs 49.2, p < 0.001) and have less time elapsed from their fellowship graduation (20.37 vs 22.64 years, p < 0.001). Patients who saw high volume doctors (OR 1.95, CI 1.65–2.31) and were seen in high volume facilities (OR 1.40, CI 1.18–1.65) were more likely to undergo MIS RH compared to abdominal RH. Patients who underwent MIS RH were more likely to be discharged home as opposed to acute rehab or nursing facility, when compared to patients treated with abdominal RH (98.5 vs 94.2% p < 0.001). When analyzing perioperativce outcomes, patient undergoing MIS RH had a 85% decrease in length of hospital stay compared to abdominal RH, a 40% reduction in 30-day readmission rates, and a 10% reduction in hospital costs respectively.DiscussionIn our study period, between the years of 2007 and 2015, the number of cervical cancer cases treated with MIS RH increased from 25.7% to 48.3%. MIS techniques led to a reduction in length of hospital stay, patient readmission rates, and hospital costs. Based on recent data from Ramirez et al., preliminary data demonstrated decrease in MIS RH for treatment of cervical cancer after presentation of the LACC trial and our data confirmed these reported trends in NYS. With this change in surgical practice, there will be associated changes in perioperative outcomes. Moreover, for patients diagnosed with cervical cancer with microscopic disease or previous treatment with an excisions procedure, MIS approach should be considered for improvement in perioperative outcomes as long as oncologic outcomes are not compromised.     

Exploiting antitumor immunity to overcome relapse and improve remission duration

Cancer survivors often relapse due to evolving drug-resistant clones and repopulating tumor stem cells. Our preclinical study demonstrated that terminal cancer patient's lymphocytes can be converted from tolerant bystanders in vivo into effective cytotoxic T-lymphocytes in vitro killing patient's own tumor cells containing drug-resistant clones and tumor stem cells. We designed a clinical trial combining peginterferon α-2b with imatinib for treatment of stage III/IV gastrointestinal stromal tumor (GIST) with the rational that peginterferon α-2b serves as danger signals to promote antitumor immunity while imatinib's effective tumor killing undermines tumor-induced tolerance and supply tumor-specific antigens in vivo without leukopenia, thus allowing for proper dendritic cell and cytotoxic T-lymphocyte differentiation toward Th1 response. Interim analysis of eight patients demonstrated significant induction of IFN-γ-producing-CD8(+), -CD4(+), -NK cell, and IFN-γ-producing-tumor-infiltrating-lymphocytes, signifying significant Th1 response and NK cell activation. After a median follow-up of 3.6 years, complete response (CR) + partial response (PR) = 100%, overall survival = 100%, one patient died of unrelated illness while in remission, six of seven evaluable patients are either in continuing PR/CR (5 patients) or have progression-free survival (PFS, 1 patient) exceeding the upper limit of the 95% confidence level of the genotype-specific-PFS of the phase III imatinib-monotherapy (CALGB150105/SWOGS0033), demonstrating highly promising clinical outcomes. The current trial is closed in preparation for a larger future trial. We conclude that combination of targeted therapy and immunotherapy is safe and induced significant Th1 response and NK cell activation and demonstrated highly promising clinical efficacy in GIST, thus warranting development in other tumor types.     

Taxol: an important new drug in the management of epithelial ovarian cancer.

Taxol, an antineoplastic agent isolated from the Pacific yew, has been demonstrated in three phase 2 clinical trials to have major activity (30 percent overall response rate) in patients with ovarian cancer refractory to cisplatin. The major toxicities associated with the agent are neutropenia (dose-limiting), hypersensitivity reactions, peripheral sensory neuropathy, and cardiac arrhythmias. A recently reported phase 1 trial of the combination of cisplatin and taxol has defined acceptable doses for the two-drug combination to be tested against cisplatin and cyclophosphamide as frontline therapy of advanced ovarian cancer. Taxol has also been examined for intraperitoneal administration in patients with ovarian cancer, with a major pharmacokinetic advantage for peritoneal cavity exposure being demonstrated. Unfortunately, any future development of taxol as an antineoplastic agent in the management of ovarian cancer will be dependent on the finding of an alternative source of the drug, as the current method of obtaining taxol from the bark of the Pacific yew provides insufficient quantities for large-scale clinical use.     

Whole abdominal radiotherapy in ovarian cancer

Objectives

The aim of the study was to evaluate the clinical outcome and toxicity after adjuvant whole abdominal radiotherapy (WART) in patients with ovarian cancer.

Material and methods

Ten patients with optimal cytoreduced ovarian cancer, with a mean age of 58 years (40–70) and stage Ic: 4, stage II: 2, stage III: 4, were treated with WART and adjuvant chemotherapy (9/10). The total radiation dose was 22.5 Gy in the whole abdomen and 42–45 Gy in the pelvis.

Results

The mean follow-up was 8 years. The 5-year actuarial disease-free survival (DFS) was 60%, and the overall survival (OS) was 70%. Four patients had disease recurrence. The sites of recurrence were the abdomen in 2 patients and distant metastases in the other 2 patients (liver and brain metastasis). Gastrointestinal toxicity was as follows: acute 3/10 grades I and II, and late toxicity: 2/10 grades I and II, and only 1 patient developed small bowel obstruction (SBO) that required surgery.

Conclusions

Whole abdominal radiotherapy after surgery and platinum-based chemotherapy achieves high locoregional disease control with an acceptable risk of acute toxicity.     

Vagotomy for Gastric Ulcer

Out of a series of 75 patients who were treated by vagotomy and drainage for gastric ulcer 66 have been followed up for one to seven years (average three-and-a-half years). Four recurrent gastric ulcers occurred among the 33 cases of ulcer of the lesser curve or body with no antral or duodenal lesion (type I). Among the 42 patients with an antral ulcer or an associated active or healed pyloric or duodenal lesion (type II or III) there was only one recurrence. The recurrence rate for men was 5% and for women 12%. One patient died two years after operation from cancer which may have originated in the stomach. The clinical results in patients without recurrences were generally satisfactory.Vagotomy, preferably selective, with drainage is a satisfactory operation in gastric ulcers of types II and III. For ulcers of type I, gastrectomy is to be preferred except in selected cases.